The current classification of psychiatric disorders is based on categorical clustering of signs and symptoms, without regard to underlying neurobiologic mechanisms. The reification of these categories has constrained efforts to develop an understanding of the fundamental behavioral, neural and genetic mechanisms that give rise to various forms of psychopathology. To address this disconnect between mechanism and nosology, the NIMH recently launched the RDoC project to facilitate a more bottom up approach to psychopathology. Our proposal focuses on the negative valence domain of the RDoC matrix and aims to characterize and validate a neural phenotype of the Anxiety construct (response to potential threat). In a uniquely large neuroimaging resource (the MGH Genomic Superstruct Project, GSP) we have recently identified a neural measure of limbic system integrity (amygdala enlargement and medial prefrontal cortical [mPFC] thinning) that is robustly associated with dimensional measures of trait anxiety. Consistent with the goals of the RDoC framework, we now propose to validate key biological and clinical features of this anxiety dimension in three stages: 1) Clinical Characterization: we will demonstrate the relevance of this neural phenotype to clinical populations presenting with significant anxiety symptoms and its association with symptom severity, chronicity and functional impairment; 2) Neural Dissection: we will use advanced Connectome imaging technology to examine the relationship between the anxiety neural phenotype and white matter connectivity between the mPFC and specific amygdala subnuclei; and 3) Genetic Dissection: using common and rare (exome array) genomewide data (N = 2078), we will conduct single variant, genome partitioning, and biological pathway analyses to identify allelic contributions to the anxiety neural phenotype and characterize the aggregate heritability and biological significance of contributing loci. Successfu completion of these aims will yield novel insights into the neural, behavioral, and genetic basis of the RDoC anxiety dimension and provide a crucial step towards the RDoC's goal of a new framework for psychiatric classification grounded in etiology and pathogenesis.